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Acute flaccid paralysis (AFP) is a clinical syndrome characterized by rapid onset of weakness, including (less frequently) weakness of the muscles of respiration and swallowing, progressing to maximum severity within several
days to weeks. The term "flaccid" indicates the absence of
spasticity or other signs of disordered central nervous system motor tracts such as hyperreflexia, clonus, or extensor
plantar responses (1). When applied to voluntary muscles,
"paralysis" means loss of contraction due to interruption of
motor pathways from the cortex to the muscle fiber. It is
preferable to use the term "paresis" for slight loss of motor
strength and "paralysis" or "plegia" for severe loss of motor
strength (1). The differential diagnosis of AFP varies considerably with age. No single operational clinical case definition of AFP or paralytic poliomyelitis that combines both
high sensitivity and high specificity has emerged (2-4). The
currently used case definition increases sensitivity in detecting the existence of AFP but tends to decrease specificity in
detecting paralytic poliomyelitis.
INTRODUCTION
298
res
1
Muscle biopsy
Myasthtnia
BotuKcm.
Tttanus, Drugs
Polymyoitte,
Toodc mycpathy,
ICU mycpathy
FIGURE 1. Algorithm for the evaluation of patients with limb or respiratory weakness. NMJ, neuromuscular junction; CK, creatine kinase;
AMAN, acute motor axonal neuropathy; AIDP, acute inflammatory demyelinating polyneuropathy; ICU, intensive care unit.
299
condition,
r, or agent
or horn cells of
spinal cord
omyelitis
Pain
Pleocytosis
in
cerebrospinal
fluid
Nerve
conduction
study
Paralysis in 1% of the
infected; nonspecific
prodrome (abortive
poliomyelitis)
Incubation period
7-14 days
(4-35 days)
Yes
No
Yes
Rare
+/-
Yes
Yes
Hand-foot-and-mouth
disease, aseptic
meningitis, AHCt
As in poliomyelitis
As in poliomyelitis
Yes
No
Yes
None
+/-
Yes
Yes
As in poliomyelitis
Reduced
CMAP
amplitude
As in poliomyelitis
As in poliomyelitis
Yes
No
Yes
None
+/-
Yes
Yes
As in poliomyelitis
Reduced
CMAP
amplitude
Months to years
Acute, symmetrical,
ascending
No
Yes
Yes
Yes
+/-
Yes
No
Incubation period
10-21 days
Acute, symmetrical,
ascending
Yes
Yes
Yes
No
+/-
+/-
+/-
Yes
Incubation period
5-15 days
Acute, proximal,
asymmetrical
Yes
+/-
+/-
No
Yes
+/-
+/-
Yes
Abno
Reduced
CMAP amp.
Preceding infection,
bilateral facial
weakness
Hours to 10 days
Acute, symmetrical,
ascending
(days to 4 weeks)
No
Yes
+/-
No
No
Yes
+/-
No
Reduced
CMAP
amplitude,
demyelination
Fulminant, widespread
paralysis, bilateral
facial weakness,
tongue involvement
Hours to 10 days
1-6 days
No
No
Yes
No
Yes
Yes
No
Dene
Reduced
p
CMAP
ti
amplitude,
axonal degeneration
Subacute ascending
hypotonic
+/-
Yes
Yes
Yes
Yes
Yes
F30SSil
Yes
Yes
No
Yes
No
Axonal
degeneration
te motor
xonal neuopathy
'"
and rt
...ma_.
symptoms
Reduced
or
ReMenin- absent sidual
bladder
gismus
deep
paralydystendon
sis
function
reflexes
Progression
of paralysis
neurotropic
viruses
bies virus
n-Barrd
syndrome
te inflammaory polyradicloneuropathy
Onset of
paralysis
Clinical
findings
cine-associated
aralytic poliomyelitis
cella-zoster
irus
omegalovirus
olyradiculomyelopathy
traumatic
sciatic neuritis
amuscular
Acute, asymmetrical
luteal injection
Hours to 4 days
Complete, affected
limb
No
Ele
myo
Dene
npolio enteroirus
Fever
at
onset
Dene
Dene
Sciat
d
v
nsverse myelitis
transverse
Preceding Mycoplasma
pneumoniae,
litis
Schistosoma, other
parasitic or viral
infection
al abscess
In severe cases,
palatal paralysis,
blurred vision
Incubation period
1-8 weeks
(paralysis
8-12 weeks
after onset
of illness)
Abdominal pain,
diplopia, loss of
accommodation,
mydriasis
Incubation period
18-36 hours
nskia
mboldtiana,
alderoni
Hours to days
Yes
Normal
Norm
Yes
Yes
Yes
Yes
Yes
Yes
+/-
Moderate
Normal
Norm
No
Yes
Severe
Yes
Yes
Yes
+/-
Moderate
Normal
Norm
Yes
Yes
No
No
No
Yes
+/-
Demyelination
No
No
No
No
No
Facilitation
with repetitive
stimuli
No
No
Yes
Yes
No
Reduced
CMAP
amp.
No
No
No
No
Yes
+/-
+/-
+/-
Weeks to months
after tick
exposure
Subacute, multifocal
Yes
Yes, increased
protein
Late
d
v
Norm
d
v
Dene
Decrement Norm
on rep.
stimulus
Multifocal
No
No
No
No
No
No
No
No
Sudden,
complete
Hours to days:
prolonged
blockade
No
No
No
Yes
No
Yes
No
No
Weeks to months
No
No
Yes
No
No
Yes
No
Normal or
Myop
reduced
CMAP
Hours to days
Yes
No
Yes
No
No
No
No
Normal or
Myop
reduced
CMAP
Yes
No
Yes
No
No
No
No
Normal or
Myop
reduced
CMAP
Weakness, fatigability,
diplopia, ptosis,
dysarthria
Preceding gastroenteritis
Yes
No
Erythema migrans,
bilateral facial
paralysis, cardiac
abnormalities
nosis
Yes,
early
Yes
borreliosis
apsing fever)
myositis
No
No
Acute, symmetrical
ascending
Yes
Acute, symmetrical
ascending
Latency period
5-10 days
rs of muscle
myositis
Yes
No
Ocular symptoms
epolarizing
gs
Yes
Rapid, descending,
symmetrical
te paralysis
s of the
euromuscular
unction
henia gravis
Yes
of Clostridbotulinum
Hours to days
Complete
Complete
cord
pression;
ma
thies
xin of
ynebacum
htheriae
Acute, lower
limbs symmetrical,
hypotonia/
lower limbs
Table cont
302
Marx et al.
II
CO
l<
!o
<
|u
COCO
CD
tr
CC
3fflO
Cj>
OC
I
a:
<
iff!
CO
CO
o
2
J
^P
CO
o
8g
s
o
2.
of
i 2 E
2 CO
11
|O
o<
If
CO
to >,
sf
I?
E 2
SB
|S
"D &
3 2
Q;
1
c
uo
UJ
CD
<
CO
S E
I?
O CD
5 O )
IS
2g
co .2
fe 53 5
O O C
1*
'--
If
52
IU
303
Myasthenia, Botulism,
Tetanus, Neuromuscular
Blocking Agents,
Plant and Snake Toxins
Myelin:
AIDP, Diphtheria
Muscle:
Polymyositis,
Toxic Myopathy,
ICU Myopathy
FIGURE 2. Pathophysiologic mechanisms and anatomic sites of etiologic factors for acute flaccid paralysis. CMV, cytomegalovirus; AMAN,
acute motor axonal neuropathy; AMSAN, acute motor-sensory axonal neuropathy; AIDP, acute inflammatory demyelinating polyneuropathy;
ICU, intensive care unit. (Adapted with permission from Ho et al. (99)).
Neuromuscular Junction:
304
Marx et al.
sion and eradication of wild poliovirus. Since a live attenuated strain of the virus is used in oral poliovirus vaccine,
the Sabin-derived virus may occasionally revert to a
neurovirulent strain, potentially causing paralytic illness
that is clinically identical to poliomyelitis resulting from
wild-type virus. The overall risk of vaccine-associated
paralytic poliomyelitis in the United States and Latin
America is one case per 2.5 million oral poliovirus vaccine
doses; the risk in Romania is one case per 183,000 oral
poliovirus vaccine dosesa 14-fold increased risk (49,
50). Three distinct groups are at risk of vaccine-associated
disease: recipients of oral poliovirus vaccine (mostly
infants receiving their first dose), persons in contact with
oral poliovirus vaccine recipients (mostly unvaccinated or
inadequately vaccinated adults), and immunocompromised
individuals (51). However, neither HIV infection nor AIDS
has been associated with an increased risk of paralytic disease due to wild-type or Sabin-derived poliovirus (52).
There is no long-term carrier state in infected immunocompetent persons, regardless of the clinical course.
However, prolonged shedding of Sabin-derived poliovirus
has been shown to occur in immunocompromised patients
with B-cell deficiencies (53).
Nonpolio enteroviruses. Nonpolio enteroviruses have
been associated with polio-like paralytic disease, frequently
accompanied by other clinical syndromes, such as aseptic
meningitis, hand-foot-and-mouth disease, and acute hemorrhagic conjunctivitis. Coxsackieviruses A and B, echovirus
(54), enterovirus 70 (24, 55), and enterovirus 71 (56-65)
have been implicated in polio-like paralytic disease.
Outbreaks of acute hemorrhagic conjunctivitis with radiculomyelitis and paralytic illness in India, Taiwan, Thailand,
and Panama were etiologically linked to enterovirus 70 (24,
55). Muscle weakness and wasting associated with
enterovirus 70 is usually severe and permanent (24).
Among all known nonpolio enteroviruses, enterovirus 71
has been most strongly implicated in outbreaks of central
nervous system disease and AFP, first described in
California during 1969- 1973 (60). Global attention focused
on enterovirus 71 when severe epidemics of central nervous
system disease occurred in Japan in 1973 (56) and in
Bulgaria in 1975 (57). Of 705 patients infected with
enterovirus 71 in Bulgaria, 149 (21 percent) developed
paralysis, and 44 (29 percent) of those persons died. Young
children under 5 years of age were most frequently affected.
Further outbreaks were reported in Hungary in 1978 (63)
and in Philadelphia, Pennsylvania, in 1987 (59). Household
clusters of acute neurologic disease associated with
enterovirus 71 were reported among children in Brazil in
1988-1990 (62). The most recent outbreaks were reported in
Malaysia in 1997 (66) and in Taiwan in 1998 (64, 65).
Antecedent illness (7-14 days before onset of AFP) was
generally characterized by fever, vomiting, diarrhea,
lethargy, nuchal rigidity, irritability, and anorexia; at 60-day
follow-up, these patients suffered from residual paralysis
with weakness and muscle wasting (67). Although signs of
polio-like illness were found less frequently in AFP patients
with isolation of nonpolio enterovirus than in polioviruspositive patients, nonpolio enterovirus infection may be
Epidemiol Rev Vol. 22, No. 2, 2000
305
306
Marx et al.
ACUTE MYELOPATHIES
Acute transverse myelitis
As a cause of AFP, acute transverse myelitis is less frequent than Guillain-Barre syndrome or paralytic nonpolio
enterovirus infection; the reported annual incidence is less
than one case per 2 million population (104). The common presentation includes, in the initial phase of spinal
shock, weakness of the lower extremities, AFP, urinary
distention (neurogenic bladder), constipation, hyporeflexia, sensory impairment (sensory level), severe pain,
and paresthesia. After 2-3 weeks, hyperreflexia and spasticity appear. Among patients with acute transverse
myelitis, approximately one third fully recover, one third
partially recover, and the rest remain disabled or die
(105).
Acute transverse myelitis has been associated with M.
pneumoniae, Herpesviridae (cytomegalovirus, Epstein-Barr
virus, varicella-zoster virus), rabies virus, hepatitis A virus,
and enteric fever. Parasitic infection may involve the spinal
cord or brain stem, including Schistosoma mansoni and
Schistosoma haematobium, Cysticercus cellulosae, Taenia
solium and Taenia multiceps, Echinococcus granulosus
(cystic hydatid disease) and Echinococcus multilocularis,
and paragonimiasis (104). Cases of acute transverse myelitis
have been documented following administration of oral
poliovirus vaccine, tetanus toxoid (DT, Td), and cholera,
typhoid fever, and plasma-derived hepatitis B virus vaccine,
but the evidence has been considered inadequate to confirm
Epidemiol Rev Vol. 22, No. 2, 2000
307
308
Marx et al.
PERIPHERAL NEUROPATHIES
Toxic neuropathies
Anatomically, two broad categories of peripheral neuropathy can be distinguished in terms of the pattern of involvement of the peripheral nervous system: 1) polyradiculoneuropathies involve the spinal roots and peripheral nerve trunks,
and 2) poly neuropathies, which result in bilaterally symmetrical disturbance of function, tend to be associated with agents
that act diffusely on the peripheral nervous system, such as
toxic substances, deficiency states, systemic metabolic disorders, and certain types of autoimmune reactions.
Toxic neuropathies are an important group of disorders in
neurologic practice in the tropics. Distal axonal degeneration ("dying back phenomenon") is the neuronal dysfunction in most toxic neuropathies (13). Neuropathies may
occur in the course of infectious diseases, such as diphtheria, borreliosis, and rabies. Acute peripheral neuropathy
with features similar to those of Guillain-Barre syndrome
can occur in acute beriberi, acute intermittent porphyria,
AIDS, paralytic rabies, cytomegalovirus infection, EpsteinBarr virus infection (110), and hepatitis B virus infection,
and following the administration of Semple-type rabies vaccine (69) (see section on rabies vaccines above).
309
310
Marxetal.
311
312
Marxetal.
Host or environmental factors may considerably influence the occurrence and frequency of AFP. For instance, the
ability to metabolize certain drugs or compounds may vary
between certain populations (isoniazid toxicity in Japan;
thyrotoxic periodic paralysis mostly among Asian, Latin,
and Native American men). The spread of C. jejuni infections, in conjunction with host, dietary, and sanitary factors,
may account for summertime epidemics of AMAN without
geographic clustering in northern China. The spread of
potential vectors determines the occurrence of tickborne
paralysis or borreliosis (Lyme disease, relapsing fever)
causing GuiUain-Barre syndrome-like AFP. The geographic
distribution of genetically determined neuromuscular diseases may be influenced by genetic factors, while environmental factors may be associated with nonhereditary
immunologic myopathies and neuropathies. Exposure to
manmade or naturally occurring toxins, such as those found
in toxic plants (e.g., K. humboldtiana, K. calderoni), venomous animals (e.g., snakes, scorpions, frogs), contami-
AFP is a complex clinical syndrome that requires immediate and careful evaluation of the differential diagnoses.
Each case of AFP is an emergency, from both a clinical perspective and a public health perspective, and precise knowledge of the etiology, underlying pathophysiologic mechanisms, and anatomic-morphologic changes involved has
profound implications for prognosis and treatment. The
underlying pathology, precise cellular basis, or pathophysiologic mechanisms for certain causes of AFP are not yet
understood. The examples of Guillain-Barre' syndrome, neurologic complications in AIDS, acute transverse myelitis,
and Hopkins syndrome illustrate the complex and multifactorial interaction between different pathogenic factors,
including preceding or concurrent infection with neurotropic agents, along with inadequate immune or autoimmune responses of the nervous system. Infections with neurotropic viruses and other infectious agents may set in
motion a pathologic immune process that inappropriately
targets central or peripheral myelin or peripheral axons (8,
99). The association between infection with C. jejuni, M.
pneumoniae, S. mansoni, or 5. haematobium and a variety of
causes of AFP, such as AIDP, AMAN, Hopkins syndrome,
and acute transverse myelitis, is intriguing and has drawn
considerable research interest. The role of infectious agents
and immune processes as significant causes of AFP may be
complemented by a variety of naturally occurring or manmade toxins.
The list of underlying causes of AFP is broad, and there is
substantial variation by age, ethnicity, and geographic area.
In the absence of wild virus-induced poliomyelitis, the acute
demyelinating form of Guillain-Barr6 syndrome (AIDP)
accounts for at least 50 percent of AFP cases globally (16,
77), followed in frequency by paralytic nonpolio enterovirus
infection, the motor axonal form of Guillain-Barre syndrome (AMAN), traumatic neuritis, and acute transverse
myelitis.
The campaign to eradicate poliomyelitis is at a critical
stage. The smallpox eradication program demonstrated the
need for accurate surveillance, while a factor contributing to
the failure of earlier eradication programs was the absence
of the capacity to establish surveillance meeting these high
standards. Without accurate disease surveillance, it is
impossible to conduct an effective disease control or eradication program or to measure the disease burden and the
effect of intervention measures.
Because poliomyelitis is on the verge of eradication,
accurate surveillance for AFP must be intensified. The
global incidence rate of nonpolio AFP would be expected to
be 1 per 100,000 among children under 15 years of age
under conditions of optimal surveillance with complete case
ascertainment (78). Achieving and maintaining this detection rate is considered the most sensitive performance criterion for any AFP surveillance system. Epidemiologic and
Epidemiol Rev Vol. 22, No. 2, 2000
ACKNOWLEDGMENTS
The authors thank Dr. Peter Strebel, Dr. Muireann
Brennan, Dr. Bernard Moriniere, and Dr. Gina Tambini for
technical advice; Jeff Colby and Patricia Smith for graphic
assistance; and Jessie Aukes, Onnalee Henneberry, Pam
Martin, Matthew Nwosu, and Katherine Tucker for assistance in searching the literature.
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